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Published on: July 17, 2013
Microbicidal protein psoriasin is a multifunctional modulator of neutrophil activation
Yan Zheng1, François Niyonsaba, Hiroko Ushio
1Department of Dermatology, Atopy Allergy Research Centre, Juntendo University School of Medicine, Tokyo, Japan.
Abstract:
As effector cells in host defence, neutrophils actively destroy invading microorganisms via a potent antimicrobial arsenal composed of oxidants and antimicrobial peptides. Psoriasin, an Escherichia coli-cidal antimicrobial protein, has been found to be overexpressed in psoriasis, a skin disease characterized by infiltration of neutrophils. In addition to its microbicidal activities and chemotaxis of neutrophils reported previously, we hypothesized that psoriasin might regulate other neutrophil functions such as cytokine and chemokine production, reactive oxygen species generation, and release of antimicrobial peptides. In the current study, we demonstrate that psoriasin activates neutrophils to produce a range of cytokines and chemokines including interleukin-6 (IL-6), IL-8/CXCL8, tumour necrosis factor-alpha, macrophage inflammatory protein-1alpha (MIP-1alpha)/CCL3, MIP-1beta/CCL4 and MIP-3alpha/CCL20. Furthermore, psoriasin induces phosphorylation of mitogen-activated protein kinase p38 and extracellular signal-regulated kinase (ERK), but not c-Jun N-terminal kinase (JNK), both of which are required for the production of cytokines and chemokines as evidenced by the inhibitory effects of p38 and ERK inhibitors on psoriasin-mediated neutrophil activation. Moreover, psoriasin stimulates the generation of reactive oxygen species from neutrophils, most likely via nicotinamide adenine dinucleotide phosphate oxidase activation. Finally, we demonstrate that psoriasin enhances messenger RNA expression of alpha-defensins, termed human neutrophil peptides (HNP) 1 to 3, and induces their extracellular release. Besides its antimicrobial properties, therefore, psoriasin may contribute to innate immunity through enhancing neutrophil host defence functions at sites of inflammation or infection.
Insights
Psoriasin, an antimicrobial protein, activates neutrophils to enhance host defense. It stimulates cytokine/chemokine release, reactive oxygen species generation, and antimicrobial peptide expression, contributing to innate immunity.
Area of Science:
- Immunology
- Dermatology
- Microbiology
Background:
- Neutrophils are key effector cells in host defense, utilizing antimicrobial peptides and oxidants.
- Psoriasin, an Escherichia coli-cidal protein, is overexpressed in psoriasis and known to have microbicidal and neutrophil chemotaxis activities.
- Previous research suggested psoriasin might influence other neutrophil functions beyond direct antimicrobial action.
Purpose of the Study:
- To investigate the role of psoriasin in regulating neutrophil functions, including cytokine/chemokine production, reactive oxygen species (ROS) generation, and antimicrobial peptide release.
- To elucidate the signaling pathways involved in psoriasin-mediated neutrophil activation.
- To determine if psoriasin contributes to innate immunity by modulating neutrophil effector functions.
Main Methods:
- Neutrophil activation assays measuring cytokine and chemokine production (e.g., IL-6, IL-8/CXCL8).
- Western blotting to assess mitogen-activated protein kinase (MAPK) phosphorylation (p38, ERK, JNK).
- Measurement of reactive oxygen species (ROS) generation and alpha-defensin (human neutrophil peptide, HNP 1-3) mRNA expression and release.
Main Results:
- Psoriasin significantly activated neutrophils to produce key cytokines and chemokines (IL-6, IL-8/CXCL8, TNF-alpha, MIP-1alpha/CCL3, MIP-1beta/CCL4, MIP-3alpha/CCL20).
- Psoriasin induced p38 and ERK phosphorylation, crucial for cytokine/chemokine production, while JNK was not affected.
- Psoriasin stimulated ROS generation, likely via NADPH oxidase, and enhanced HNP 1-3 mRNA expression and release.
Conclusions:
- Psoriasin modulates neutrophil functions beyond its direct antimicrobial activity.
- Psoriasin enhances neutrophil-mediated innate immunity by promoting pro-inflammatory cytokine/chemokine release, ROS production, and antimicrobial peptide expression.
- Psoriasin's multifaceted effects on neutrophils suggest a significant role in host defense at sites of inflammation and infection.
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